Supplementary Figure 1. Basic functional characterization of B10G5 antibody. Supplementary Figure 2. Changes in serum levels of cytokines and chemokines with depletion of lymphocyte subsets during B10G5 therapy. Supplementary Figure 3. Anti-sMIC mAb B10G5 therapy significantly increase homeostatic proliferation of adoptively transferred NK cells. Supplementary Figure 4. B10G5 therapy did not impact CD4 T cell homeostasis but increased T-bet expression. Supplementary Figure S5. Undetectable endogenous SV40TAg epitope I-specific CD8 T cells shown by lack of positive staining by H-2Db-restrcited TAg epitope I-specific tetramer (Db/I-Tetramer). Supplementary Figure 6. Anti-sMIC mAb B10G5 therapy inhibits the growth of transplantable TRAMP-sMICB tumors. Supplementary Figure 7. Anti-sMIC therapy enhanced antigen-specific CD8 T cell responses in the transplantable TRAMP-C2-sMICB-OVA tumor model. Supplementary Figure 8. Therapeutic effect of B10G5 against well-differentiated TRAMP/MICB tumors. Supplementary Figure S9. Representative flow cytometry analyses demonstrating that depletion of NK cells during B10G5 therapy impairs CD4 T cell Th1 responses.
ARTICLE ABSTRACT
Purpose: The human tumor-derived soluble MHC I-chain–related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model.Experimental Design: We treated the engineered MIC-expressing “humanized” TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms.Results: A sMIC-neutralizing nonblocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T-cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive.Conclusions: Therapy with a sMIC-neutralizing nonblocking anti-MIC mAb can effectuate antitumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies. Clin Cancer Res; 21(21); 4819–30. ©2015 AACR.
